CKD: Calcium-Based Phosphate Binders May Increase Mortality

Laurie Barclay, MD

July 24, 2013

Compared with calcium-based phosphate binders, non-calcium-based phosphate binders are associated with a lower risk for all-cause mortality in patients with chronic kidney disease (CKD), according to a systematic review and meta-analysis published online July 19 in the Lancet.

"The results of this study support what most clinical researchers in the field suspected," Professor Markus Ketteler, MD, FERA, division head of Nephrology, Klinikum Coburg, Germany, told Medscape Medical News when asked for independent comment. "As already recommended by the [Kidney Disease Improving Global Outcomes] guidelines on CKD-mineral and bone disorders, use of calcium-based binders should at least be restricted in patients at risk for hypercalcemia and vascular calcification. We do not yet know whether there is a safety threshold for maximally tolerable doses of calcium-containing binders enabling reasonable combinations of different binders."

To update their 2009 meta-analysis on the effect of calcium-based vs non-calcium-based phosphate binders on mortality in patients with CKD, Sophie A. Jamal, MD, and colleagues from the University of Toronto performed a systematic review of articles published from August 1, 2008, to October 22, 2012. They searched Medline, Embase, International Pharmaceutical Abstracts, Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing and Allied Health Literature.

Inclusion criteria were publications in any language describing randomized and nonrandomized trials comparing outcomes for patients with CKD taking calcium-based vs non-calcium-based binders. The DerSimonian and Laird random effects models allowed evaluation of all-cause mortality as a primary outcome by pooling data from randomized trials.

Of 847 reports identified, 8 new studies met selection criteria, including 5 randomized trials. These were added to the 10 studies (9 randomized trials) included in the previous meta-analysis.

In 11 randomized trials (4622 participants) reporting mortality as an outcome, patients receiving non-calcium-based binders had a 22% reduction in all-cause mortality compared with those receiving calcium-based phosphate binders (risk ratio, 0.78; 95% confidence interval, 0.61 - 0.98).

Strong Evidence Favors Noncalcium Binders

"This systematic review shows the complete picture regarding available data on the risks and benefits of calcium-free vs calcium-containing phosphate binders in the CKD population," Dr. Ketteler said. "The sample size is large with a relevant number of events. The evidence suggesting superiority of calcium-free phosphate binders in the treatment of hyperphosphatemia in CKD patients is quite strong."

However, he also noted various limitations, including those inherent in the original studies. For example, the available data did not allow separation of cardiovascular from all-cause mortality or determination of a specific risk profile for each phosphate binder.

The investigators concur that further studies are needed to identify causes of mortality and to examine whether mortality differs by type of non-calcium-based phosphate binder.

"Even with the results of this systematic review, we do not know if calcium-free binders are particularly beneficial or if calcium-containing binders are immediately harmful in the treatment of hyperphosphatemia in CKD patients," Dr. Ketteler said. "There [are] economical implications, because favored use of calcium-free binders will raise the costs of CKD treatment."

He recommends a randomized, placebo-controlled trial on hard outcomes targeting phosphate retention in a population of patients not receiving dialysis with serum phosphate levels in or modestly above the high-normal range.

"Leaving dialysis patients with profound hyperphosphatemia untreated [would] be unethical, given this systematic review and a large body of epidemiological and pathobiological data," Dr. Ketteler concluded. "Outcomes should be mortality and cardiovascular events, possibly progression to end-stage renal disease. Selection of [participants] could be additionally guided by levels of FGF23, a hormone regulating phosphate balance in health and disease."

In an accompanying comment, Alberto Ortiz, MD, PhD, from the Nephrology and Hypertension Department, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz and Universidad Autónoma de Madrid, Instituto Reina Sofía de Investigación Nefrológica, Spain, and Maria Dolores Sanchez-Niño, PhD, from the Nephrology Department, Instituto de Investigación Hospital Universitario La Paz, La Red de Investigación Renal, Madrid, Spain, call this study a potential "game-changer."

"Physicians' perception of the cost-effectiveness of phosphate-binder choices might change following this meta-analysis and the expected cost reduction after patents for non-calcium-based phosphate binders start expiring in 2014."

One coauthor received honoraria for speaking engagements for Sanofi; one is on advisory boards for Genzyme and Amgen and has received a speaking honorarium from Amgen; one is a consultant for Gore, Roche, and Takeda; and one has received consulting fees from Genzyme. The other authors have disclosed no relevant financial relationships. The investigators report no external funding for the analysis. Dr. Ortiz has received consultancy fees, honoraria, and speakers' fees from Sanofi, Genzyme, Fresenius Medical Care, and Amgen; research funding or funding for equipment or drugs from Fresenius Medical Care; and travel or accommodation payments from Genzyme, Fresenius Medical Care, Shire, Amgen, Baxter, Rubió and Abbott. Dr. Sanchez-Niño has received consultancy fees, honoraria, and speakers' fees from Genzyme. Dr. Ketteler received honoraria from Abbvie, Amgen, Genzyme/Sanofi, Shire, Medice, Fresenius Medical Care, Mitsubishi, and Vifor as a speaker and/or consultant.

Lancet. Published online July 19, 2013. Article abstract, Comment extract

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